Our data reveal a critical and largely unstudied role for the sympathetic nervous system (SNS) in regulating the overall efficacy of radiation therapy (RT), by signaling through norepinephrine-driven activation of ?-adrenergic receptors. Our preliminary data reveal that adrenergic stress signaling blunts the response of the irradiated tumor to RT through at least two pathways: a) Impairment of the anti-tumor immune response, limiting the ability of radiation to control non-irradiated distant tumors (abscopal effect) in vivo and b) increasing intrinsic resistance of tumor cells to radiation in vitro. These data support the exciting hypothesis that a simple and novel strategy, combining RT with ?-adrenergic receptor (?-AR) antagonists (i.e., ?-blockers) significantly and safely enhances the sensitivity of tumor cells to radiation therapy and stimulates anti-tumor immunity. We have chosen to test this hypothesis by taking an innovative approach in which two separate teams, at Roswell Park Comprehensive Cancer Center and University of Rochester Medical Center, with complimentary expertise in radiation, stress biology, and tumor immunology will collaborate to optimize pre- clinical protocols combining RT with ?-blockers and to identify key underlying cellular and molecular mechanisms. The aims are: Aim 1: Test the hypothesis that the overall response to radiation (in both primary irradiated tumors and distant, non-irradiated tumors) is regulated by signaling through ?-ARs. We will use several different and clinically relevant tumor models in different strains of mice and different radiation protocols, to define the dependence of radiation efficacy on ?-AR signaling. Importantly, we have valuable ?-AR knockout mice to help pinpoint the role of host adrenergic signaling. Aims 2 and 3 will evaluate indirect and direct mechanisms by which adrenergic stress could be regulating the efficacy of radiation. Aim 2 will evaluate the role of immunological and physiological factors in the tumor microenvironment, including analysis of how combinations of radiation and immunotherapy with anti-PD-1, are influenced by the addition of ?- blockers. Aim 3 will evaluate whether adrenergic stress signaling can directly influence the sensitivity of tumor cells to radiation and cytotoxic cells by altering the balance of pro-and anti-apoptotic molecules or whether other pathways that govern tumor cell sensitivity to killing are involved. A constant flow of real-time information between our teams should result in optimized protocols that enhance confidence that our data concerning the impact of blockade of adrenergic signaling on radiation therapy are predictive of patients? response. Performing simultaneous experiments, using different models and RT protocols in two different centers, will enable us to test more tumor models, and increase rigor, transparency and reproducibility of our overall conclusions. Overall, this will produce the strongest data to facilitate the design of large randomized studies at both centers.